Tablets incorporating isoflavone plant extracts and methods of manufacturing them

ABSTRACT

The invention is directed to novel tablets comprising isoflavone-containing plant extract and water-insoluble polysaccharides, and methods of manufacturing them.

FIELD OF THE INVENTION

The invention is generally related to the fields of pharmaceuticals,compressed tablet formulations and methods of manufacturing tablets. Inparticular, the invention is directed to novel tablets comprisingisoflavone-containing plant extract, particularly, extracts from fruitsof plants from the Leguminosae family, and water-insolublepolysaccharides, and methods of manufacturing same.

BACKGROUND OF THE INVENTION

Isoflavones are naturally occurring glucosides found in many plants,particularly soybeans. As soybean is a rich protein source and soy isused as a dietary supplement, isoflavones are found in many foods anddrinks. Isoflavone-containing soy proteins are used in the food industryto replace or extend meat, milk, egg, and other protein sources intraditional food products. One of the key factors limiting the use ofsoy protein concentrate, especially in nutritional beverages, milkreplacers, and dairy products, is the soy taste present in the finalproduct. Soy concentrates are also not widely used in nutritionalbeverages, milk replacers, and dairy products because of the presence ofsoy fiber as an insoluble component, causing an undesirable “mouthfeel.”Administration of isoflavone-containing concentrates, as plant extracts,in the form of a tablet would eliminate undesirable “mouthfeel” andtaste problems. However, isoflavone-containing plant extracts, becauseof their unique physiochemical properties, have not been reported tohave been successfully formulated into a pressed tablet that candisintegrate in a reasonably short period of time. It has been achallenge to formulate isoflavone-containing plant extracts into presseddisintegratable tablets.

Even more significant than their use as a dietary supplement is thefinding that isoflavones have many potential pharmaceutical uses. Forexample, isoflavones have been reported to be possible anti-canceragents, see, e.g., Messina (1991) J. of the American Cancer Institute83:542-545; Charland (1998) Int J Mol Med 2:225-228. Daidzein andgenistein glucuronides, major isoflavone metabolites, may be partlyresponsible for the anti-cancer biological effects of isoflavones due totheir estrogen receptor binding ability and natural killer (NK) cellactivation, see, e.g., Zhang (1999) J Nutr 129:399-405; Lu (1998) Am. J.Clin. Nutr. 68(6 Suppl):1500S-1504S. Soy genistein has been reported tobe a chemopreventive agent against breast and prostate cancer in humans,see, e.g., Peterson (1991) Biochem. Biophysical Res. Corn. 179:661-667;Peterson (1993) Prostate 22:335-345. Isoflavone, an isoflavonesynthesized from soy daidzein, is being tested to prevent and treatosteoporosis and other metabolic bone diseases, see, e.g., Head (1999)Altern. Med. Rev 4:10-22. Atherosclerosis was reduced in animals feddiets containing soy protein compared with those fed diets with animalprotein; the components of soy protein that lower lipid concentrationsare extractable by alcohol, i.e., they include the isoflavones genisteinand daidzein (see, e.g., Anthony (1998) Am. J. Clin. Nutr. 68(6Suppl):1390S-1393S.) It is also believed that daidzein and itsmetabolites, o-desmethylangolensin and dihydrodaidzein, are useful foraltering the concentration of cholesterol constituents in the blood byincreasing the concentration of high-density lipoprotein cholesterol anddecreasing the concentration of low density lipoprotein cholesterol,see, e.g., Potter, et al., U.S. Pat. No. 5,855,892. However, to date itis not economical to administer these isoflavone components andmetabolites in any purified form. Thus, the only economically practicalmeans to administer these agents are as plant extracts, i.e.,isoflavone-containing plant extracts, from, e.g., fruits of leguminousplants such as soybeans, red clover, Schigandra, and the like.

It would be preferable to administer plant extracts as compressed(solid) tablets for oral administration due to reasons of stability,economy, simplicity and convenience of dosing. However, most plantextracts (including isoflavone-containing plant extract), because oftheir unique physiochemical properties, are difficult to formulate intoa compressed tablet form capable of dissolving in the stomach in areasonably short period of time (e.g., a disintegration time at leastabout 30 minutes in gastric fluid). The difficulties in manufacturingplant extract-containing pressed tablet products are due to theirphysiochemical properties. The extracts contain fine particles thatcause poor flow of the formulation and affects tablet compression.

Furthermore, the gel-forming nature of the plant extract makes itdifficult to obtain a tablet with a reasonable disintegration time(e.g., at least about 30 minutes in gastric fluids). For example, soyplant extract, when exceeding 50% by weight in a tablet, tends to retardthe disintegration time even in the presence of normally very efficient“super-disintegrants,” such as croscarmellose sodium. It is thehygroscopicity of the plant extract that has impeded development of aone-tablet-per-dose formula using a direct compression approach.

Thus, there exists a great need for plant extract-containing compressedtablets with sufficient hardness to withstand packaging and handling,yet able to be administered orally, i.e., capable of dissolving in anaqueous environment similar to that found in the stomach (i.e., gastricjuices) in a reasonable period of time (about 30 minutes or less). Itwould further be advantageous if such tablets could be madeeconomically. The present invention fulfills these and other needs.

SUMMARY OF THE INVENTION

This invention provides for the first time pressed tablets comprisingisoflavone-containing plant extracts, and methods of manufacturing them,that have advantageous physical-chemical properties and are economicalto produce.

The invention provides physiologically acceptable tablets comprising anisoflavone-containing plant extract and a compressed tablet formulationthat comprises a water-insoluble polysaccharide, wherein the amount ofthe water-insoluble polysaccharide in the tablet comprises at leastabout 15% of the dry weight of the tablet. In alternative embodiments,the water-insoluble polysaccharide is a plant water-insolublepolysaccharide, the plant water-insoluble polysaccharide is a soybeanplant water-insoluble polysaccharide, and the soybean plantwater-insoluble polysaccharide is Emcosoy® polysaccharide. In oneembodiment, the isoflavone-containing plant extract is from the fruit ofa plant from the Leguminosae family, and, in a preferred embodiment, asoy bean extract.

In alternative embodiments, the water-insoluble polysaccharide in theinvention's tablets comprise between about 15% to about 25% of the dryweight of the tablet; and between about 21% to 22% of the dry weight ofthe tablet.

In other embodiments, the amount of the isoflavone-containing plantextract in the tablets comprise between about 10% to about 85%, about20% to about 75%, about 30% to about 70%, and about 45% to about 65% ofthe dry weight of the tablet.

In one embodiment, the tablets can dissolve in a gastric fluid within atleast about 30 minutes; in a preferred embodiment, the tablets candissolve in less than about 15 to 16 minutes.

The tablets of the invention can further comprise a micronized fattyacid, which, in alternative embodiments, is present in the tablet atamounts between about 1% to about 5% of the dry weight of the tablet,and, about 2% of the dry weight of the tablet. The tablets of theinvention can further comprise a silica gel, which, in alternativeembodiments, is in an amount between about 1% to about 5% of the dryweight of the tablet, and, about 2% of the dry weight of the tablet. Ina preferred embodiment, the micronized fatty acid is a micronizedstearic acid.

In various embodiments, the tablets of the invention are suitable fordelivery to a body cavity, including the oral, buccal or sublingualcavities, and swallowing. The tablet formulations of the invention canfurther comprise at least one additive agent, including, e.g., adisintegrant, a flavorant, an artificial sweetener, a perfume, and acolorant.

The invention also provides tablets made by a direct compression (“dryblend”) process comprising the following steps: (a) mixing an initialformulation comprising an isoflavone-containing plant extract, awater-insoluble polysaccharide (e.g., Emcosoy® polysaccharide), whereinthe amount of the water-insoluble polysaccharide in the tablet comprisesat least about 15% of the dry weight of the tablet, a filler, and, asilica gel glidant, wherein the amount of the silica gel in the tabletcomprises between about 1% to about 5% of the dry weight of the tablet;(b) milling the mixed formulation; (c) mixing into the milled and mixedformulation a micronized fatty acid (e.g., a micronized stearic acid),wherein the amount of the micronized fatty acid in the tablet comprisesbetween about 1% to about 5% of the dry weight of the tablet; and, (d)pressing the milled formulation into a tablet form, wherein thecompression force of the press on the tablet is at least about 15kilopounds. In alternative embodiments, in the dry blend process, thecompression force of the press on the tablet is between about 15 toabout 30 kilopounds, and between about 17 to about 23 kilopounds. Inthese tablets, the isoflavone-containing plant extract can be an extractfrom the fruit of a Leguminosae family plant, e.g., a soy plant bean.

The tablets of invention manufactured by the dry blend process canfurther comprise a coating made by: (a) coating the pressed tablets withan aqueous dispersion comprising a cellulose-based polymer; (b) dryingthe coated tablets, wherein the drying does not heat the tablet morethan up to about 40° C.

The invention also provides tablets made by a granulation processcomprising the following steps: (a) mixing an initial formulationcomprising an isoflavone-containing plant extract and a water-insolublepolysaccharide (e.g., Emcosoy® polysaccharide), wherein the amount ofthe water-insoluble polysaccharide in the tablet comprises at leastabout 15% of the dry weight of the tablet; (b) granulating the mixedformulation using an aqueous solution comprising at least about 0.5%cellulose-based polymer; (c) drying the granulated formulation; and (d)pressing the dried, granulated formulation into a tablet form. In thesetablets of the invention, the isoflavone-containing plant extract can bean extract from the fruit of a Leguminosae family plant, e.g., soy bean.

The tablets of the invention manufactured by the granulation process canfurther comprise a coating made by (a) coating the pressed tablets withan aqueous dispersion comprising a cellulose-based polymer; (b) dryingthe coated tablets, wherein the drying does not heat the tablet morethan about 40° C.

The invention also provides a direct compression (“dry blend”) processfor producing a tablet comprising the following steps: (a) mixing aninitial formulation comprising an isoflavone-containing plant extract, awater-insoluble polysaccharide (e.g., Emcosoy® polysaccharide), whereinthe amount of the water-insoluble polysaccharide in the tablet comprisesat least about 15% of the dry weight of the tablet, a filler, and asilica gel glidant wherein the amount of the silica gel in the tabletcomprises between about 1% to about 5% of the dry weight of the tablet;(b) milling the mixed formulation; (c) mixing into the milled and mixedformulation a micronized fatty acid (e.g., a micronized stearic acid),wherein the amount of the micronized fatty acid in the tablet comprisesbetween about 1% to about 5% of the dry weight of the table; and, (d)pressing the milled formulation into a tablet form, wherein thecompression force of the press on the tablet is at least about 15kilopounds. In this process, the isoflavone-containing plant extract canbe from the fruit of a Leguminosae family plant, such as a soy beanextract. In one embodiment in this process, the compression force of thepress on the tablet is between about 17 to about 23 kilopounds.

This dry blend process can further comprises a coating processcomprising the following steps: (a) coating the pressed tablets with anaqueous dispersion comprising a cellulose-based polymer; (b) drying thecoated tablets, wherein the drying does not heat the tablet more thanabout 40° C.

The invention further provides a granulation process for producing atablet comprising the following steps: (a) mixing an initial formulationcomprising an isoflavone-containing plant extract and a water-insolublepolysaccharide (e.g., Emcosoy® polysaccharide), wherein the amount ofthe water-insoluble polysaccharide in the tablet comprises at leastabout 15% of the dry weight of the tablet; (b) granulating the mixedformulation using an aqueous solution comprising at least 0.5%cellulose-based polymer; (c) drying the granulated formulation; and (d)pressing the dried, granulated formulation into a tablet form.

This granulation process can further comprise a coating processcomprising the following steps: (a) coating the pressed tablets with anaqueous dispersion comprising a cellulose-based polymer; (b) drying thecoated tablets, wherein the drying does not heat the tablet more thanabout 40° C.

The invention also provides a physiologically acceptable tabletcomprising a compressed tablet formulation that comprises anisoflavone-containing plant extract, wherein the amount of theisoflavone-containing plant extract in the tablet comprises about 45% toabout 65% of the dry weight of the tablet; a filler, a micronized fattyacid (e.g., a micronized stearic acid), wherein the amount of themicronized fatty acid in the tablet comprises between about 1% to about5% of the dry weight of the tablet; a silica gel glidant, wherein theamount of the silica gel in the tablet comprises between about 1% toabout 5% of the dry weight of the tablet; a water-insolublepolysaccharide (e.g., Emcosoy® polysaccharide), wherein the amount ofthe water-insoluble polysaccharide in the tablet comprises at leastabout 15% of the dry weight of the tablet, and wherein the tablet cansubstantially dissolve in a gastric fluid in, in alternativeembodiments, at least about 15 minutes and at least about 30 minutes.

A further understanding of the nature and advantages of the presentinvention may be realized by reference to the remaining portions of thespecification, the figures and claims.

All publications, patents and patent applications cited herein arehereby expressly incorporated by reference for all purposes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for novel pharmaceutically acceptabletablets. Also provided are methods of making such tablets. The inventionprovides new formulations and manufacturing processes that overcome theproblems that had previously prevented the formulation ofisoflavone-containing plant extract into a pressed tablet, while at thesame time achieving the optimal balance between the physical propertiesneeded for manufacturing and handling, e.g., hardness, and the tablet'sdisintegration characteristics (particularly, in the gastric fluid ofthe stomach), in addition to other advantageous properties.

The invention uses water-insoluble polysaccharides (e.g., Emcosoy® athigh usage levels (about 22% by weight) in the manufacturing processesof isoflavone plant extract containing tablets. In one embodiment,pressed tablets with a disintegration time of less than 16 min. aremanufactured. This amount of water-insoluble polysaccharide is novel tothe invention, as it is greater than accepted manufacturing practice(the supplier-recommended usage level for Emcosoy® soy polysaccharidesin tablets is only 4% to 10%).

Definitions

The term “artificial sweetener” as used herein incorporates the term'scommon usage and refers to any synthetic composition that sweetens thetaste of a formulation.

The term “cellulose based polymer” refers to any polymeric cellulose,synthetic or derived or isolated from a natural source, such as, e.g., ,hydroxypropyl cellulose; hydroxypropylmethyl cellulose; hydroxyethylcellulose; methyl cellulose; cellulose acetate; or other cellulose basedwater soluble polymers.

The term “coating” refers to any material or composition added to thecore tablet. For example, in one embodiment, a coating is added to thepressed “core” tablets of the invention by spraying the tablet with anaqueous dispersion comprising a cellulose based polymer.

The term “colorant” as used herein incorporates the term's common usageand refers to any composition that adds color to a formulation,including the core tablet or the coating.

The terms “compressing,” “pressing,” “molding” and “press molding” referto the process of applying compressive force to a formulation (powder orgranules), as within a die, to form a tablet. The terms “compressedtablet” and “pressed tablet” mean any tablet formed by such a process.

The term “drying” and “dried” refer to a process which decreases thewater content of a composition, as the drying of a humidified tablet.The term “dried tablet” refers to a tablet that has been treated in anymanner to decrease the amount of water in the formulation. For example,in one embodiment, the formulation of the invention is manufactured intotablet form using a granulation process, and a tablet is dried after itsinitial granulation and compression into a tablet form. In anotherembodiment, pressed “core” tablets of the invention are coated with anaqueous dispersion, which is subsequently dried.

The term “dry weight” as used herein incorporates the its common usageand, in the context of the tablets of the instant invention, means theweight of a tablet after substantially all the water (or other solutionor solvent) has been removed from the tablet.

The term “formulation” refers to any mixture of compositions used tomake the tablets of the invention, including both core tablet andcoating material.

The term “disintegrant” as used herein incorporates the term's commonusage and refers to any composition which decreases the disintegrationtime (accelerates the rate of disintegration) of a tablet.

The term “filler” as used herein incorporates the term's common usageand refers to any inert material or composition added to a formulationto add bulk.

The term “flavorant” as used herein incorporates the term's common usageand refers to any composition which adds flavor to or masks the badtaste or smell of a formulation.

The term “gastric fluid” as used herein means any fluid havesubstantially the same properties as fluids found in the stomach,including “simulated” gastric fluid, as described below.

The term “granulating” refers to the process of blending and mixing aformulation in an aqueous solution, as described infra.

The term “isoflavone-containing plant extract” as used hereinincorporates the term's common usage and refers to naturally derivedisoflavone-containing plant extracts and comparable syntheticisoflavone-containing compositions. Isoflavone-containing plant extractsare typically derived as natural products from plants, e.g., fruits ofplants from the Leguminosae family (i.e., fruits of leguminous plants),such as the soy bean, see, e.g., Crank, et al., U.S. Pat. No. 5,858,449.The term includes relatively crude plant extracts containing isoflavoneand relatively purified and isolated components thereof, including allisoflavone glycoside components, as described in further detail below.In one embodiment, fruits of the Leguminosae family, particularly soybeans, are a preferred source of isoflavone plant extract.

The terms “leguminous plant” and “plant of the Leguminosae family”incorporate their common usage, such as detailed herein, infra.

The terms “micronized fatty acid” and “micronized stearic acid” refersto a fatty acid powder and a stearic acid powder, respectively, wheremore than about 90% of the particles in the powder have a particle sizeof less than about 30 to 50 microns (for example, they are both fattyacid powders which have been passed through a #325 mesh screen). In oneembodiment, the micronized stearic acid is the commercially availableTri Star, NF (Sego International, Inc., Portland, Oreg.).

The term “perfume” refers to any composition that contributes to theodor or taste, or masks an unpleasant smell, of a formulation.

The term “physiologically acceptable” refers to any combination ofmaterials or compositions that are not harmful, i.e., non-toxic, tocells and tissues under physiologic (in vivo) conditions.

The term “polysaccharide” refers to any polysaccharide, or derivativethereof, from any natural or synthetic sources. The term“water-insoluble polysaccharide” refers to a polysaccharide polymericcomposition insoluble in an aqueous solution. For example, in oneembodiment, the water insoluble polysaccharide is the commerciallyavailable Emcosoy® polysaccharide (Penwest Pharmaceuticals, Co.,(formerly Mendell), Patterson, N.Y.).

The term “silica gel” as used herein means a glidant which conforms tothe specifications for Silicon Dioxide contained in the United StatesPharmacopeia/National Formulary (USP/NF) and the Food Chemical Codex(FCC).

The term “soy plant” or “soybean plant” means any plant from theLeguminosae family, e.g., Glycine max.

The term “tablet” is used in its common context, and refers to a solidcomposition made by compressing and/or molding a mixture of compositionsin a form convenient for swallowing or application to any body cavity.

Isoflavone-Containing Plant Extracts

In nature, isoflavone-containing plants primarily are legumes, clovers,the root of the kudzu vine (pueraria root), and Schigandra.Isoflavone-containing plants appear to be widely distributed in theplant kingdom. Over 700 different isoflavones have been described.However, the most common source of isoflavone plant extract is from thefruits (e.g., beans, peas) of the Leguminosae family, including, e.g.,soy beans and chick peas. Clover sources of isoflavone plant extractinclude red clover and subterranean clover. In one embodiment, fruits ofthe Leguminosae family, particularly soy beans, are a preferred sourceof isoflavone plant extract.

In raw plant material, isoflavones occur principally as glycosides. Theisoflavones in vegetable protein whey include isoflavone glucosides(glucones), isoflavone conjugates, and aglucone isoflavones. Isoflavoneglucosides have a glucose molecule attached to the isoflavone moiety ofthe compound. Isoflavone conjugates have additional moieties attached tothe glucose molecule, for example, 6″-OAc genistin contains an acetategroup attached to the six position of the glucose molecule. Agluconeisoflavones consist of an isoflavone moiety without an attached glucosemolecule. Soy whey contains three “families” of isoflavone compoundshaving corresponding glucoside, conjugate, and aglucone members: thegenistein family, the daidzein family, and the glycitein family. Thegenistein family includes the glucoside genistin; the conjugates 6″-OMalgenistin (6″-malonate ester of genistin) and 6″-OAc genistin (6″-acetateester of genistin); and the aglucone genistein. The daidzein familyincludes the glucoside daidzin; the conjugates 6″-OMal daidzin, and6″-OAc daidzin; and the aglucone daidzein. The glycitein family includesthe glucoside glycitin, the conjugate 6″-OMal glycitin, and the agluconeglycitein.

Isoflavone-containing plant extract can be made from any leguminousplants in addition to the soybean plant (Glycine max), such as, e.g.,Indian liquorice (Abrus precatorius); various species of Acacia spp.including, A. aneura, A. cibaria, A. longifolia, and A. oswaldii; groundnut (Apio tuberosa); ground pea (Arachis hypogea); milk vetch(Astragalus edulis); marama bean (Bauhinia esculenta); sword bean(Cajanus cajan indicus); jack bean (Canavalia ensiformis); sword bean(Canavalia gladiata); seaside sword bean (Canavalia rosea); variousCassia spp. including C. floribunda, C. laevigata, and C. occidentalis;carobbean (Ceratonia siliqua); chick pea (Cicer arietinuin); yebnut(Cordeauxia edulis); various Crotalaria spp. including C. laburnifolia,and C. pallida; cluster bean (Cyamopsis psoralioides); tallow tree(Detariaum senegalense); sword bean (Entada scandens); balu (Erythrinaedulis); inga (Ingaedulis); Polynesian chestnut (Inocarpus fagifer);hyacinth bean (Lablab purpureus); grass pea or Indian vetch (Lathyrussativus); cyprus vetch (Lathyrus ochrus); lentil (Lens culinaris);jumping bean (Leucaenal eucocephala); various Lupinus spp. including L.albus, L. luteus, L. angustifolium, L. mutabilis, and L. cosentinii;ground bean (Macotylma geocarpa); horse gram (Macrotyloma uniflorum);alfalfa (Medicago sativa); velvet bean (Mucuna pruriens); yam beans(Pachyrhyzuz erosus, P. tuberosus); African locust bean (Parkiaclappertoniana); Parkia speciosa; oil bean tree (Pentaclethramacrophylla); various Phaseolus spp. including P. acutifolius, P.vulgaris, P. luntus, P. coccineus, P. adenathus, P. angulris, P. aureus,P. calcaratus, P. mungo, and P. polystachyus; garden pea (Pisumsativum); djenko bean (Pithecolobium lobatum); mesquite (variousProsopis spp.); goa bean (Psophocarpus scandens, P. tetragonolobus);various Psoralea spp.; Sesbania bispinosa; yam bean (Sphenostylisstenocarpa); tamarind (Tamarindus indica); fenugreek(Trigonellafoenum-graecum); vetches (various Vivia spp. including V.sativa, V. atropurpurea, V. ervilia, and V. monantha); broad bean (Viciafaba); black gram (Vigna mungo); various Vigna spp. including V.radiata, V aconitifolia, V. adanatha, V. angularus, V. tribolata, V.umbelata, and V. unguiculata; and, earth pea (Voandzeia subterranea).

Isoflavone-containing plant extract can be processes and isolated fromany plant source in which it naturally occurs. For example, isoflavonesmay be isolated from red clover as disclosed by e.g., Wong (1962) J.ScL. Food Agr., Vol. 13, p. 304. Isoflavones may be isolated fromsoybean as described by, e.g., Potter, et al., U.S. Pat. No. 5,855,892;Shen, et al.; U.S. Pat. No. 5,851,792; Kelly, et al. U.S. Pat. No.5,830,887; Waggle, et al., U.S. Pat. No. 5,821,361. Isoflavones may beisolated from molds, e.g., from Micrornonospora halophytica (see, e.g.,Ganguly (1970) Chem. & Ind. (London), p. 201).

Alternatively, isoflavones can be synthetically prepared, see, e.g.,Baker et al , J Chem. Soc., p. 274 (1933); Wesley et al., Ber. Vol. 66,p. 685 (1933); Mahal et al., J. Chem. Soc., p. 1769 (1934); Baker etal., J. Chem. Soc., p. 1852 (1953); Farkas, Ber. Vol. 90, p. 2940(1957), and Potter, et al., U.S. Pat. No. 5,855,892. A process forconverting isoflavone glucosides to aglucone isoflavones in a vegetableprotein whey is described in PCT/US/94/10699. See also, Kanaoka, et al.,U.S. Pat. No. 5,847,108.

Isoflavones and isoflavone-containing plant extracts are alsocommercially available. Soy plant-derived material from which isoflavonecan be isolated include, e.g., soy beans, dehulled soy beans, soy meal,soy flour, soy grits, soy flakes (full fat and defatted), soy molasses,soy protein concentrate, soy whey, soy whey protein, and soy proteinisolate. Isoflavones can be extracted from any of these soy materialswith a low molecular weight organic extractant, e.g., an alcohol (e.g.,aqueous ethyl alcohol or methyl alcohol), ethyl acetate, acetone, orether. The extractant can have a pH of about the isoelectric point ofsoy protein (about pH 4 to pH 5) to minimize the amount of soy proteinextracted by the extractant. The extractant containing the isoflavonescan be further separated from insoluble soy materials to form anisoflavone enriched extract. Impurities in the extract can be separatedout by contacting the extract with a material which adsorbs theisoflavones in the extract, and eluting the adsorbed isoflavones out ofthe adsorbent material with a solvent which causes the isoflavones to bedifferentially eluted from the adsorbent material.

Tablet Formulation

The invention provides a physiologically acceptable compressed tabletcomprising a formulation that includes an isoflavone-containing plantextract, particularly, an extract from the fruit of a leguminous plant,and a water-insoluble polysaccharide, where the amount of thewater-insoluble polysaccharide in the tablet comprises at least about15% of the dry weight of the tablet. In alternative embodiments, thetablet can also contain micronized fatty acid, fillers, and/or glidants(e.g., silica gel glidants).

Water Insoluble Polysaccharides

For the first time the invention provides tablets and methods ofmanufacturing them using water-insoluble polysaccharides. Use of thewater-insoluble polysaccharide solves a long-felt need to formulateisoflavone-containing plant extracts into a pressed tablet form that hassufficient hardness to be packaged and handled by the consumer and yetstill be able to disintegrate in an aqueous solution (e.g., a bodyfluid, such as gastric fluid) within 30 minutes after being used (e.g.,swallowed). Without the water-insoluble polysaccharide, the pressedtablet would not be able to disintegrate in less than 30 minutes afterexposure to the aqueous solution. In fact, manufacturers ofwater-insoluble polysaccharides (e.g., Penwest Pharmaceuticals, Co.,Patterson, N.Y.) recommend that the amount of soy polysaccharride (thewater-insoluble polysaccharide used in a preferred embodiment of theinvention) used in making a tablet should be between 4% to 10%. However,this would result in a pressed core tablet with unacceptable properties(i.e., a tablet that could not disintegrate in less than 30 minutes inan aqueous solution). In summary, the invention's first use ofwater-insoluble polysaccharide at higher concentrations than wereconsidered standard manufacturing practice solves a problem seen in themanufacturing and use of isoflavone plant extract-containing pressedtablets. Thus, the tablets and methods of the invention differ fromrecommended manufacturing practices.

Water-insoluble polysaccharides can be isolated from any source. Acommon and economical source is soy. Water-insoluble polysaccharides arecommonly derived from soy as insoluble dietary fiber, see, e.g.,Fredstrom (1991) JPEN JParenter. Enteral Nutr. 15:450-453.Water-insoluble polysaccharides are also commercially available, and maybe purchased, e.g., from Penwest Pharmaceuticals, Co., Patterson, N.Y.,as the product Emcosoy® soy polysaccharide.

One skilled in the art using routine and well-known methods can readilydetermine whether any polysaccharide has the required property of being“water-insoluble” and thus, useful in the manufacture of the tablets ofthe invention.

Other Formulation Components

Lubricants help in the manufacturing of a tablet; e.g., they helpprevent “ejection sticking” of compressed formulation to the pressingdies and punches. “Ejection sticking” is a particularly difficultproblem when a formulation comprising isoflavone-containing plantextract is pressed into tablets by the dry blend process (discussed infurther detail below). This difficulty is for the first time overcome bythe invention's use of micronized fatty acid, such as a micronizedstearic acid. In one embodiment, the amount of the micronized fatty acidin the tablet comprises between about 1% to about 5% of the dry weightof the tablet.

Furthermore, without use of micronized fatty acids, use of anisoflavone-containing plant extract in a pressed tablet formulation willresult in unacceptable blistering, cracking or delamination of the finalproduct. The problems of blistering, cracking and delamination weresolved by using silica gel, micronized stearic acid and the multiplemilling process of the invention.

In an alternative embodiment, the tablets of the invention canoptionally include additional lubricants, such as the insolublelubricant magnesium stearate, or a derivative thereof. The magnesiumstearate can be between 0.1% and 2.0%, or between 0.5% and 1.0%, of theweight of the tablet.

In another embodiment, disintegrants are also included in theformulations of the invention. For example, non-saccharide water solublepolymers, such as crosslinked povidine, can be added to the formulationto further enhance the rate of disintegration. Other disintegrants thancan also be used include, e.g., croscarmellose sodium, sodium starchglycolate, and the like; see, e.g., Khattab (1992) J. Pharm. Pharmacol.45:687-691.

The tablets of the invention can further comprise any medicament, drug,palliative, nutritive, or pharmaceutically active material, e.g., adrug, medicament, nutrient, placebo, and the like. However, theinvention is broadly applicable to a wide variety of isoflavone plantextract-containing tablets for uses in addition to those discussed above(e.g., anti-cancer, atherosclerosis, dietary supplement), including, butnot limited to, tablets for, e.g., antacids, gastrointestinal agents,analgesics, antiinfectives, CNS-active agents, cardiovascular agents,cough therapies, vitamins, and other pharmaceutical, nutritional anddietary agents.

Any colorant can be used, as long as it is approved and certified by theFDA. For example, exemplary colors include allura red, acid fuschin D,naphtalone red B, food orange 8, eosin Y, phyloxine B, erythrosine,natural red 4, carmine, to name a few. The most common method of addingcolor to a tablet formulation is to dissolve the dye in solution priorto the granulating process.

Sweetening agents can be added to the tablet formulation (in the coretablet and/or just the coating solution) to create or add to thesweetness. Saccharide fillers and binders, e.g., mannitol, lactose, andthe like, can add to this effect. For example, cyclamates, saccharin,aspartame, acesulfame K (Mukherjee (1997) Food Chem. Toxicol.35:1177-1179), or the like (Rolls (1991) Am. J. Clin. Nutr. 53:872-878),can be used. Sweeteners other than sugars have the advantage of reducingthe bulk volume of the tablet (core tablet and/or coat) and noteffecting the physical properties of the tablet.

Manufacturing Processes

The invention provides for methods of manufacturing the isoflavone plantextract-containing tablets of the invention. In preferred embodiments,the tablets are manufactured by a direct compression process and agranulation process. Both of these processes generate a “core tablet.”which can, in an alternative embodiment, be further processed to add a“coating” which can contain, e.g., cellulose-based polymers, coloringagents, flavorants, and the like.

The Direct Compression Process of Manufacture

The steps involved in the manufacture of an isoflavone plantextract-containing “core tablet” by a direct compression, or “dryblend,” process comprise a mixing (blending) step, a milling step (andin one embodiment, a second mixing step), and a pressing step. In oneembodiment, the core tablet is further processed and a “coating” isadded in a two-step process; a coating step and a drying step. All ofthese processing steps require no more than conventional processing andmanufacturing equipment.

Mixing Step

In the direct compression (“dry blend”) manufacturing process, aninitial formulation of components of the tablet, including anisoflavone-containing plant extract and a water-insoluble polysaccharide(in an amount resulting in it being at least 15% of the dry weight ofthe tablet), are mixed. In alternative embodiments, a micronized fattyacid is added in this initial formulation, or, after the milling step,or both. In either case, the amount of micronized fatty acid added tothe formulation is sufficient to ensure that it will comprise betweenabout 1% to about 5% of the dry weight of the tablet. Isoflavone plantextract-containing formulations which use conventional lubricant(s) inplace of micronized fatty acid cannot be pressed into tablet forms in adry blend compression process without significant “sticking” problems,i.e., the formulation sticking on the press punches. This problem isparticularly acute when rotary tablet presses are used.

In one embodiment, a filler (e.g., microcrystalline cellulose), aglidant (e.g., a silica gel), or both are added to the initialformulation before or during mixing. Alternatively, either or both(filler or glidant) can be added after milling. The amount of silica geladded to the tablet is sufficient to ensure that it will comprisebetween about 1% to about 5% of the dry weight of the tablet.

In other embodiments, either before or after milling, additionalcomponents can be added to the formulation, e.g., a filler (such asmicrocrystalline cellulose) or glyceryl behenate. Glyceryl behenatereduces problems such as capping, sticking or delamination associatedwith the use of other lubricants (e.g., regular grade stearic acid,magnesium stearate) in a similar formulation. However, glycerol behenatecannot replace micronized fatty acid to prevent isoflavone plantextract-containing formulations from sticking on tablet press punches(as discussed above). In one embodiment, the formulation is mixed withabout 13 to about 15 parts (by weight) of microcrystalline cellulose andone to two parts glyceryl behenate.

Milling Step

The initial formulation, after mixing, is milled using conventionaltechniques and machinery. In alternative embodiments, the initialformulation mixture is milled through a 20-mesh and a 30-mesh screenusing commercially available milling equipment such as, e.g., Quadro® orComil® (Quadro, Millburn, N.J.).

Compression, or “Pressing,” Step

The pressing or compression of the formulation after the milling stepand, in some embodiments, after an additional mixing step, can beaccomplished using any tablet press. Many alternative means to effectthis step are available, and the invention is not limited by the use ofany particular equipment. In a preferred embodiment, the compressionstep is carried out using a rotary type tablet press. The rotary typetableting machine has a rotary board with multiple through-holes, ordies, for forming tablets. The formulation is inserted into the die andis subsequently press-molded.

The diameter and shape of the tablet depends on the die and punchesselected for the compression of the milled and mixed formulation.Tablets can be discoid, oval, oblong, round, cylindrical, triangular,and the like. The tablets may be scored to facilitate breaking. The topor lower surface can be embossed or debossed with a symbol or letters.

The compression force can be selected based on the type/model of press,what physical properties are desired for the tablets product (e.g.,desired, hardness, friability, in vivo disintegration or dissolutioncharacteristics, etc.), the desired tablet appearance and size, and thelike. In a preferred embodiment, the compression force of the press onthe tablet is at least about 15 kilopounds (Kp). The “core” tablets fromthe compression stage typically have a hardness of about 5 Kp to about25 Kp, with preferred embodiments having a hardness of about 11 Kp toabout 19 Kp. In other embodiments, the tablet can dissolve in a gastricfluid within at least about 30 minutes and at least about 15 minutes.

The Granulation Process of Manufacture

The steps involved in the manufacture of a isoflavone plantextract-containing “core tablet” by a granulation process comprise amixing (blending) step, a granulation step, a drying step, and acompression (or “pressing”) step. In one embodiment, the core tablet isfurther processed and a “coating” is added in a two-step process; acoating step and a drying step. All of these processing steps require nomore than conventional processing and manufacturing equipment.

Granulation Step

In the granulation manufacturing process, an initial formulation ofcomponents of the tablet, including an isoflavone-containing plantextract and a water-insoluble polysaccharide (in an amount resulting init being at least 15% of the dry weight of the tablet), are mixed. Thisinitial mixture is then blended, or “granulated,” in an aqueous solutioncomprising at least about 0.5% cellulose-based polymer. This blendingprocess is commonly called “wet granulation.” “Granulation” is commonlydefined as a size-enlargement process in which small particles aregathered into larger, permanent aggregates in which the originalparticles can still be identified. “Wet granulation” is a variation onthis process, as refers to a granulation that adds solvents and bindersto the enlargement process. See, e.g., Lipps (1993) J. Pharm. Sci.83:937-947; Olmo (1998) Drug Dev. Ind. Pharm. 24:771-778.

A variety of such blending, or mixing, or granulating, apparatus arecommonly available. For example, the granulation can be done on a FluidBed Granulator, such as the one designed by Glatt Air Techniques Inc.,N.J.

The temperature during granulation can be set at any point as long as itdoes not exceed the melting point of any components in the formulationand the balance between spraying and drying is kept. However, in apreferred embodiment, the temperature during granulation (and drying) isat a relatively low heat setting, i.e., a range of about 20° C. to about50° C. The formulation, once granulated, is dried until the temperaturereaches 40° C. before pressing into a tablet form.

Sieving and Further Mixing Steps

In other embodiments of the granulation manufacturing process, thegranulated formulation is sieved through a #20 mesh screen and a #30mesh screen.

In another embodiment, after sieving, or, if the granulated formulationis not sieved, after the granulation step, additional components can beadded to the formulation, e.g., a filler (such as microcrystallinecellulose) or glyceryl behenate. In one embodiment, the formulation ismixed with about 15 parts (by weight) of microcrystalline cellulose,and, optionally, one part glyceryl behenate. In another embodiment,either or both (the cellulose or behenate) are added in the initialmixing step.

In alternative embodiments, in addition to or in place of hydroxypropylmethyl cellulose, other hydrophilic polymers which provide a bindingeffect in granulation can also be used, e.g., polyvinyl pyrrolidone(PVP) or derivatives, polyvinyl alcohol, or hydroxypropyl cellulose ofpharmaceutical grade. The glyceryl behenate may be replaced by otherpharmaceutical lubricants such as, e.g., magnesium stearate, stearicacid, or other hydrogenated vegetable oil or triglycerides.

Compression, or “Pressing,” Step

The pressing or compression of the formulation after the granulationstep can be accomplished using any tablet press. Many alternative meansto effect this step are available, and the invention is not limited bythe use of any particular apparatus. In a preferred embodiment, thecompression step is carried out using a rotary type tablet press usingstandard manufacturing procedures, as generally described above (for thedirect compression, “dry blend,” process).

Coating Core Tablets

In alternative embodiments, core tablets of the invention made by boththe granulation and direct compression manufacturing processes arefurther treated to generate a tablet “coat.” The coating process of theinvention includes the steps of coating the pressed tablets with anaqueous dispersion comprising a cellulose-based polymer; followed bydrying the coated tablets, where the drying does not heat the tabletmore than about 40° C.

As discussed above, the coating solution can contain a variety ofingredients, including flavorants, colorants, and the like. For example,in one embodiment, the core tablet is coated with an aqueous dispersionof hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide,and a colorant. In another exemplary embodiment, the core tablet iscoated with an aqueous dispersion of hydroxypropyl methylcellulose,polyethylene glycol, and maltodextrin.

Standard manufacturing techniques and equipment are used in the coatingprocess; see, e.g., Sastry (1998) Pharm Dev Technol. 3:423-432; Parikh(1993) Pharm Res. 10:525-534.

Measuring Tablet Properties

The manufacturing methods of the invention produce a novel tabletcapable of disintegrating in a body cavity, e.g., as when taken orally(to dissolve in the gastric fluid) or to be used as a “lozenge” todissolve in the mouth; when placed onto a mucous membrane, as in thebuccal space or sublingually; intravaginally; intrarectally; and thelike.

The superior qualities (physical properties) of the tablet of theinvention can be measured, and such measurements can be used, e.g., forquality control, to compare to tablets manufactured by other processes.Physical properties can be measured using a variety of conventionalassays and tests well described in the patent, pharmaceutical andscientific literature. See, e.g., Kopp (1989) J. Pharm. Pharmacol.41:79-82. A few exemplary tests are set forth below, including means tomeasure tablet hardness, friability, disintegration time, dissolutiontime, wetting time, and porosity.

Tablet Hardness: “Crushing, ” or “Tensile” Strength

Tablet hardness is physical strength measurement of the tablet. Theresistance of a tablet to chipping, abrasion, or breakage underconditions of storage, transportation and handling before usage dependson its hardness, or “crushing strength.” The tablet “crushing” or“tensile” strength is defined as the force required to break a tablet bycompression in the radial direction. It is typically measured using oneof the many commonly available tablet hardness testers. For example,“Stokes” and “Monsanto” hardness testers measure the force required tobreak the tablet when the force generated by a coil spring is applieddiametrically to the tablet. A “Strong-Cobb” hardness tester alsomeasures the diametrically applied force required to break a tablet, theforce applied by an air pump forcing a plunger against the tablet placedon an anvil. Electrically operated hardness testers, such as theSchleuniger apparatus (also known as a “Heberlein”) can be used. Seealso, TS-50N, Okada Seiko Co., Japan; Bi (1996) Chem. Pharm. Bull.(Tokyo) 44:2121-2127.

Friability

Tablet friability is a physical strength measurement of a tablet, and isdefined as the ability of the compressed tablet to resist abrasion andattrition. It is typically measured by turning tablets in a rotatingvessel and determining weight loss (see De Jong (1987) Pharm Weekbl(Sci) 9:24-28). These rotating devices are called “friabilators.” Thefriabilator provides frictional abrasion to the tablet sample and isused to measure the resistance to abrasion or attrition of tablets. Theloss of weight is measured after a fixed number of revolutions of a drumrotating at a controlled rate.

Friabilator apparatus typically use a 285 mm drum of transparentsynthetic polymer with polished internal surfaces. One side of the drumis removable. The tablets are tumbled at each turn of the drum by acurved projection that extends from the middle of the drum to the outerwall. The drum is attached to the horizontal axis of a device thatrotates at about 25 to 30 rpm. Thus, at each turn, the tablets roll orslide and fall onto the drum wall or onto each other. Many suchapparatus are commonly available, e.g., the Roche type friabilator (VanKel Industries, Inc., Edison, N.J.); a Erweka Friability Apparatus(Erweka Instruments, Milford, Conn.) (Bi (1996) supra, Chowhan (1982) J.of Pharm. Sci. 71:1371-1375), and the like.

In one exemplary protocol, the standard United States Pharmacopia (USP)protocol for measuring friability is used. Briefly, the tablets areplaced in a friabilator that is a 285 mm drum, about 39 mm in depth, oftransparent synthetic polymer. The tablets are “tumbled” at each turn ofthe drum by a curved projection that extends from the middle of thedrum. The drum is rotated for about four minutes at about 25 rpm,resulting in a total of 100 rotations. A minimum of about 20 tablets areused in any test, unless the tablets weigh over 650 mg, in which caseonly 10 tablets are used. After the allotted time, the tablets areremoved from the friabilator, and, with the aid of air pressure or abrush, adhering particles and dust are removed, and remaining tabletsare accurately weighed. Percent loss of weight is calculated.

Measuring Disintegration Times

In measuring the disintegration time, the amount of time needed for atablet to completely disintegrate in, e.g., a test subject's stomach orin isolated gastric juice, is measured. Alternatively, simulated bodyfluids can be used, such as simulated gastric juices.

Testing for Dissolution Rate in Gastric Fluids

The invention provides for isoflavone plant extract-containingcompressed tablets that can dissolve in a gastric fluid within at leastabout 30 minutes and at least about 15 minutes. A variety of in vivo andin vitro means to evaluate and predict the dissolutionbehavior/dissolving rate of the tablets of the invention in the humanstomach, i.e., in gastric fluid, are available.

For example, means to use “simulated” gastric fluid having substantiallythe same properties as fluids found in the stomach are well known in theart, see, e.g., Huang (1999) Pharm Dev Technol 4:107-115; Lee (1998)Arch Pharm Res 21:645-650; Abu-Izza (1998) Pharm Dev Technol 3:495-501;Galia (1998) Pharm Res 15:698-705.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example 1 Manufacture of Isoflavone Plant Extract-Containing Tablets byDirect Compression Process

The following example details exemplary means to manufacture the tabletsof the invention, i.e., isoflavone plant extract-containing pressedtablets, by direct compression (“dry blend”) manufacturing techniques.

First Exemplary Tablet and Method

Core Tablets

In this exemplary direct compression (“dry blend”) manufacturing processof the invention, 61 parts of isoflavone plant extract (from a soyplant) (Indena, Seattle, Wash.) is mixed with 21 parts of waterinsoluble Emcosoy® soy polysaccharide, 13 parts of microcrystallinecellulose and 2 parts of silica gel. The mixture is milled through a12-mesh screen and mixed with 2 parts of micronized stearic acid. Themixture is pressed on a rotary laboratory scale tablet press at pressspeed of 56 RPM. Each tablet has a weight on the average of about 706mg, is oval in shape, and has a length of about 19 mm and a width ofabout 9 mm. The hardness of core tablets is about 11 Kp (determinedusing standard techniques, as discussed above).

The micronized stearic acid is unique to this invention for thesuccessful manufacture of soy isoflavone plant extract-containingtablets using a direct compression process. Other pharmaceuticallubricants such as magnesium stearate, stearic acid (regular grade) orhydrogenated vegetable oil or triglycerides cannot replace micronizedstearic acid as a lubricant in a problem-free compression process. Useof no or alternative lubricants known in the art in pressed isoflavoneplant extract-containing tablets will result in an unacceptable product,with problems that include delamination, picking or sticking. Thus, theinvention provides a solution to produce tablets containing isoflavoneplant extracts with satisfactory characteristics (i.e. adequate hardnessand reasonable disintegration time).

Water-insoluble polysaccharides serve, in part, as disintegrants in theformulation. In this invention, they were included in the formulation atunusually high levels (higher than standard manufacturing practice andhigher than recommended by the supplier (in one embodiment,water-insoluble polysaccharide is Emcosoy®; its supplier is PenwestPharmaceuticals, Patterson, N.Y.).

Coating of Tablets

In an alternative embodiment, the invention provides for the coating ofpressed core tablets. In one exemplary procedure, core tablets arecoated with an aqueous dispersion of hydroxypropyl methylcellulose,polyethylene glycol, titanium dioxide and a colorant. The coated tabletsweigh 725 mg. They disintegrated in less than 21 minutes in a simulatedgastric juice solution, as made and tested using standard United StatesPharmacopia (USP) protocols. The disintegration method used simulatedgastric fluid (as in USP) without pepsin.

Second Exemplary Tablet and Method

Core Tablets

In this exemplary direct compression (“dry blend”) manufacturing processof the invention, 53 parts of the isoflavone soy extract is mixed with21 parts of Emcosoy®, 21 parts of microcrystalline cellulose and 2 partsof silica gel. The mixture is milled through a 30-mesh screen and mixedwith 2 parts of micronized stearic acid. The mixture is then pressed ona double sided 45-station rotary press at press speed of 2400 tabletsper minute (TPM). The resultant core tablet weighs 695 mg, is oval, hasa length of about 19 mm and a width of about 9 mm. The hardness of coretablets is about 19 Kp, measured using any of the techniques, discussedabove.

The batch size in this example is about 200 Kg. This direct compressionformulation and manufacturing process is capable of a commercial scaleproduction for tablets containing soy isoflavone extract or otherisoflavone-containing plant extract or glucoside-containing material.

Coating of Tablets

In an alternative embodiment, the invention provides for the coating ofpressed core tablets. In one exemplary procedure, core tablets arecoated with an aqueous dispersion of hydroxypropyl methylcellulose,polyethylene glycol, and maltodextrin. The coated tablets weigh on theaverage about 718 mg. They disintegrated in less than about 15 minutesin a simulated gastric juice solution, as made and tested using standardUSP protocols, as discussed above (in a simulated gastric fluid withoutpepsin).

Third Exemplary Tablet and Method

Core Tablets

In this exemplary direct compression (“dry blend”) manufacturing processof the invention, 58 parts of isoflavone soy extract is mixed with 21parts of Emcosoy®, 17 parts of microcrystalline cellulose and 2 parts ofsilica gel. The mixture is milled through a 30-mesh screen and mixedwith 2 parts of micronized stearic acid. The mixture is pressed on adouble sided 45-station rotary press at press speed of 2400 TPM. Theresultant tablets weigh about 699 mg, are oval, have a length of about19 mm and a width of about 9 mm. The hardness of these core tablets isabout 19 Kp.

The batch size in this example is about 400 Kg, which was a scale-upfrom the 200 Kg process described in the second exemplary tablet andmethod, above. Thus, this example describes a direct compressionformulation and process that is capable of a commercial scale productionfor tablets containing soy isoflavone extract or otherisoflavone-containing plant extract or other glucoside-containingmaterials.

Coating of Tablets

In an alternative embodiment, the invention provides for the coating ofpressed core tablets. In one exemplary procedure, core tablets arecoated with an aqueous dispersion of hydroxypropyl methylcellulose,polyethylene glycol, and maltodextrin. The coated tablets weigh on theaverage 721 mg. They disintegrated in less than about 15 minutes in asimulated gastric juice solution, as made and tested using standard USPprotocols, as discussed above (in a simulated gastric fluid withoutpepsin).

Fourth Exemplary Tablet and Method

Core Tablets

In this exemplary direct compression manufacturing process of theinvention, the following formulation for direct compression batch wasused:

Raw Material Mg/tablet % Formula Soybean Isoflavone Extract (Indena,429.0 60.7 Seattle, WA) Soy Polysaccharides (Emcosoy ®) 156.0 22.0Microcrystalline Cellulose 101.0 14.3 Silica Gel  7.0  1.0 MagnesiumStearate  7.0  1.0 Glyceryl Behenate  7.0  1.0 Total 707.0 100.0 

The mixture of ingredients (except magnesium stearate and glycerylbehenate) from the above table is milled through a 20-mesh screen andmixed with 1 part each of magnesium stearate and glyceryl behenate. Themixture is pressed to 707 mg weight oval tablets having a length of 19mm and a width of 9 mm on a rotary laboratory scale tablet press, suchas Stokes 16-station press. The hardness of these core tablets is about19 Kp. The disintegration of tablets was less than (<) 16 min. using theUSP disintegration method in a simulated gastric fluid without pepsin.Cracking was observed but no delamination was seen on these tablets.

This example demonstrates that the water-insoluble polysaccharide (e.g.,Emcosoy® at high usage level (about 22% by weight) resulted in adisintegration time of less than 16 min. for these isoflavone-containingtablets. As noted above, this amount of water-insoluble polysaccharideis novel to the invention, as it is greater than accepted manufacturingpractice; the supplier-recommended usage level for Emcosoy® soypolysaccharides in tablets is only 4% to 10%.

The use of glyceryl behenate (1%) alone in direct compression could notprovide adequate lubrication to the blend. The addition of 1% magnesiumstearate to the blend containing 1% glyceryl behenate eliminateddelamination, however unacceptable cracking remained on the tablets.

Fifth Exemplary Tablet and Method

Core Tablets

In this exemplary direct compression (“dry blend”) manufacturing processof the invention, the following formulation for direct compression batchwas used:

Raw Material Mg/tablet % Formula Soybean Isoflavone Extract (Indena,428.6 61.2 Seattle, WA) Soy Polysaccharides (Emcosoy ®) 100.2 14.3Microcrystalline Cellulose 143.2 20.5 Silica Gel  14.0  2.0 MicronizedStearic Acid (Tri Star)  14.0  2.0 Total 700.0 100.0 

The mixture of ingredients (except micronized stearic acid) from theabove table is milled through a 14-mesh screen and mixed with 2 parts ofmicronized stearic acid. The mixture is pressed to 700 mg weight capletshaving a length of 16 mm and a width of 7 mm on a rotary laboratoryscale tablet press. The hardness of core tablets is about 16 Kp. Thedisintegration of tablets was 20 to 25 min. using the USP disintegrationmethod in a simulated gastric fluid without pepsin. There was nocracking or delamination on these tablets.

This example demonstrated that the water-insoluble (soy) polysaccharideat a high usage level (14%) resulted in disintegration time of less than25 min. for these isoflavone-containing tablets. As noted above, thesupplier recommended usage level for this soy polysaccharides is 4-10%.The use of micronized stearic acid at a level of two percent (2%)provided adequate lubrication to the blend in the direct compressionstep and eliminated delamination and cracking on tablets.

Inadequate Manufacturing Method

Core Tablets

This example is provided to illustrate that without use of the novelmethods of the invention, conventional direct compression (“dry blend”)manufacturing processes are inadequate and cannot be used to make apressed tablet containing isoflavone plant extract.

Formulation for exemplary direct compression batch Raw MaterialMg/tablet % Formula Soybean Isoflavone Extract (Indena, 429.0 66.0Seattle, WA) Microcrystalline Cellulose 170.3 26.2 Croscarmellose Sodium 32.5  5.0 Silica Gel  13.0  2.0 Magnesium Stearate   5.2  0.8 Total650.0 100.0 

The mixture of ingredients (except magnesium stearate) from the abovetable is milled through a 20-mesh screen and mixed with 0.8 parts ofmagnesium stearate. The mixture is pressed to 650 mg weight oval tabletshaving a length of 19 mm and a width of 9 mm on a rotary laboratoryscale tablet press such as Stokes 16-station press.

The hardness of core tablets is about 16 Kp. The disintegration oftablets was greater than (>) 30 min. using the USP disintegration methodin a simulated gastric fluid without pepsin. Cracking and delaminationwere observed on these tablets.

This example demonstrates that the super-disintegrant croscarmellosesodium at a normal usage level (0.5-5%) could not provide enoughdisintegration property to isoflavone-containing tablets to manufacturea useable tablet, i.e., an isoflavone tablet that dissolves in gastricfluids in less than about 30 minutes. Additionally, magnesium stearatewas not a good choice of lubricant for these isoflavone-containingtablets because it caused compression problems.

An additional exemplary core tablet formulation for direct compressionis:

Raw Material Mg/tablet % Formula Soybean Isoflavone Extract (Indena,429.0 66.0 Seattle, WA) Microcrystalline Cellulose  72.8 11.2Croscarmellose Sodium 130.0 20.0 Silica Gel  13.0  2.0 MagnesiumStearate   5.2  0.8 Total 650.0 100.0 

The mixture of ingredients (except magnesium stearate) from the abovetable is milled through a 20-mesh screen and mixed with 0.8 parts ofmagnesium stearate. The mixture is pressed to 650 mg weight oval tabletshaving a length of 19 mm and a width of 9 mm on a rotary laboratoryscale tablet press such as Stokes 16-station press. The hardness of coretablets is about 16 Kp. The disintegration of tablets was 22-25 min.using the USP disintegration method in a simulated gastric fluid withoutpepsin. Cracking and delamination were observed on these tablets.

This example demonstrates that the super-disintegrant croscarmellosesodium at unusually high usage level (20%) was still not enough to makeisoflavone-containing tablets disintegrate within 20 min. Furthermore,magnesium stearate is not a good choice of lubricant forisoflavone-containing tablets, for it caused significant compressionproblems, resulting in unacceptable cracking and delamination.

Example 2 Manufacture of Isoflavone-Containing Tablets by GranulationProcess

The following example details exemplary means to manufacture the tabletsof the invention, i.e., isoflavone-containing pressed tablets, bygranulation manufacturing techniques.

Core Tablets

In this exemplary granulation manufacturing process of the invention, 61parts of isoflavone plant extract (from a soy plant) is mixed with 22parts of Emcosoy® soy polysaccharide. The mixture is granulated in afluidized bed processor (by top-spray) using a solution of 0.6 parts ofHydroxypropyl Methylcellulose and 20 parts of water. The resultinggranules are dried. The granules are sieved and mixed with 15 parts ofMicrocrystalline Cellulose and 1 part of Glyceryl Behenate. The mixtureis then pressed on a rotary laboratory scale tablet press. The resultantcore tablet is 708 mg in weight and oval, having a length of 19 mm and awidth of 9 mm. The hardness of these core tablets is about 15 Kp.

The above described granulation process is one solution to producetablets containing isoflavone-containing plant extract using a rotarytablet press to manufacture a tablet with satisfactory characteristics(i.e. adequate hardness and reasonable disintegration time). The uniqueexcipient in the formulation is a water-insoluble polysaccharide, e.g.,from soy, e.g., Emcosoy® (supplier: Penwest Pharmaceuticals, Patterson,N.Y.). The water-insoluble polysaccharide serves, in part, as adisintegrant. As noted above, it was included in the formulation at anunusually high level, as discussed above.

Coating of Tablets

In an alternative embodiment, the invention provides for the coating ofpressed core tablets. In one exemplary procedure, core tablets arecoated with an aqueous dispersion of hydroxypropyl methylcellulose,polyethylene glycol, titanium dioxide and a colorant. The coated tabletsweigh 719 mg. They disintegrated in less than 10 minutes in a simulatedgastric juice solution, as made and tested using standard USP protocols(as discussed above).

Example 3 Coating Isoflavone-Containin2 Tablets of the Invention

The following example details exemplary means to manufacture coatedtablets of the invention.

The coating material Opadry® II Clear from Colorcon (West Point, Pa.)was used; it contains hydroxypropyl methylcellulose, polyethylene glycoland maltodextrin. The dry powder of Opadry® II Clear was dispersed inpurified water to form a 10% to 15% (weight-by-weight) film coatingdispersion.

The isoflavone-containing core tablets of the invention weresuccessfully coated with this water-based coating system under thefollowing coating conditions (otherwise, all materials and apparatus andmanufacturing techniques were conventional in the art):

Coating Parameters Range Supply Air Temperature during Spray 45-55° C.Exhaust Air Temperature during Spray 30-37° C. Solution Spray Rate670-730 ml/min Supply Air Flow Rate 2950-3450 SCFM Atomizing AirPressure 38-42 PSI

What is claimed is:
 1. A physiologically acceptable compressed tabletformulation comprising an isoflavone-containing plant extract and asoybean water-insoluble polysaccharide, wherein the amount of thesoybean water-insoluble polysaccharide in the tablet comprises at leastabout 15% of the dry weight of the tablet, and wherein said soybeanwater-insoluble polysaccharide includes cellulose, hemicellulose,pectin, gum and mucilage.
 2. The tablet of claim 1, wherein the amountof the water-insoluble polysaccharide in the tablet comprises betweenabout 15% to about 25% of the dry weight of the tablet.
 3. The tablet ofclaim 1, wherein the amount of the water-insoluble polysaccharide in thetablet comprises about 21% to 22% of the dry weight of the tablet. 4.The tablet of claim 1, wherein the isoflavone-containing plant extractis from a fruit of the Legiminosae family.
 5. The tablet of claim 4,wherein the fruit is a soy bean.
 6. The tablet of claim 1, wherein theamount of the isoflavone-containing plant extract in the tabletcomprises between about 10% to about 85% of the dry weight of thetablet.
 7. The tablet of claim 6, wherein the amount of theisoflavone-containing plant extract in the tablet comprises betweenabout 25% to about 70% of the dry weight of the tablet.
 8. The tablet ofclaim 7, wherein the amount of the isoflavone-containing plant extractin the tablet comprises about 45% to about 65% of the dry weight of thetablet.
 9. The tablet of claim 1, wherein the tablet can disintegrate ina gastric fluid within at least about 30 minutes.
 10. The tablet ofclaim 1, wherein the tablet further comprises a micronized fatty acid inan amount between about 1% to about 5% of the dry weight of the tablet.11. The tablet of claim 10, wherein the amount of the micronized fattyacid in the tablet comprises about 2% of the dry weight of the tablet.12. The tablet of claim 10, wherein the micronized fatty acid is amicronized stearic acid.
 13. The tablet of claim 1, wherein the tabletfurther comprises a silica gel in an amount between about 1% to about 5%of the dry weight of the tablet.
 14. The tablet of claim 13, wherein theamount of the silica gel in the tablet comprises about 2% of the dryweight of the tablet.
 15. The tablet of claim 1, wherein the tablet issuitable for delivery to a body cavity of the group consisting of theoral, buccal, sublingual, vaginal or rectal cavities.
 16. The tablet ofclaim 1, wherein the formulation further comprises at least one additiveagent selected from the group consisting of a disintegrant, a flavorant,an artificial sweetener, a perfume, and a colorant.
 17. A tablet made bya direct compression process comprising the following steps: (a) mixingan initial formulation comprising an isoflavone-containing plantextract, a water-insoluble polysaccharide, wherein the amount of thewater-insoluble polysaccharide in the tablet comprises at least about15% of the dry weight of the tablet, a filler, and a silica gel, whereinthe amount of the silica gel in the tablet comprises between about 1% toabout 5% of the dry weight of the tablet; (b) milling the mixedformulation; (c) mixing into the milled and mixed formulation amicronized stearic acid, wherein the amount of the micronized stearicacid in the tablet comprises between about 1% to about 5% of the dryweight of the tablet; and (d) pressing the milled formulation into atablet form, wherein the compression force of the press on the tablet isat least about 15 kilopounds.
 18. The tablet of claim 17, wherein thecompression force of the press on the tablet is between about 15 toabout 30 kilopounds.
 19. The tablet of claim 18, wherein the compressionforce of the press on the tablet is between about 17 to about 23kilopounds.
 20. The tablet of claim 17, wherein theisoflavone-containing plant extract is from the fruit of a Leguminosaefamily plant.
 21. The tablet of claim 20, wherein the fruit is a soybean.
 22. The tablet of claim 17, wherein the direct compression processfurther comprises a coating process comprising the following steps: (a)coating the pressed tablets with an aqueous dispersion comprising acellulose-based polymer; and (b) drying the coated tablets, wherein thedrying does not heat the tablet more than about 40° C.
 23. A tablet madeby a granulation process comprising the following steps: (a) mixing aninitial formulation comprising an isoflavone-containing plant extractand a water-insoluble polysaccharide, wherein the amount of thewater-insoluble polysaccharide in the tablet comprises at least about15% of the dry weight of the tablet; (b) granulating the mixedformulation using an aqueous solution comprising at least 0.5%cellulose-based polymer; (c) drying the granulated formulation; and (d)pressing the dried, granulated formulation into a tablet form.
 24. Thetablet of claim 23, wherein the isoflavone-containing plant extract isfrom the fruit of a Leguminosae family plant.
 25. The tablet of claim24, wherein the fruit is a soy bean.
 26. The tablet of claim 23, whereinthe granulation process further comprises a coating process comprisingthe following steps: (a) coating the pressed tablets with an aqueousdispersion comprising a cellulose-based polymer; and (b) drying thecoated tablets, wherein the drying does not heat the tablet more thanabout 40° C.
 27. A physiologically acceptable tablet comprising acompressed tablet formulation that comprises an isoflavone-containingplant extract, wherein the amount of the plant extract in the tabletcomprises about 45% to about 65% of the dry weight of the tablet; afiller, a micronized stearic acid, wherein the amount of the micronizedstearic acid in the tablet comprises between about 1% to about 5% of thedry weight of the tablet; a silica gel, wherein the amount of the silicagel in the tablet comprises between about 1% to about 5% of the dryweight of the tablet; and a water-insoluble polysaccharide, wherein theamount of the water-insoluble polysaccharide in the tablet comprises atleast about 15% of the dry weight of the tablet, wherein the tablet cansubstantially dissolve in a gastric fluid in at least about 30 minutes.